The goals of this project are to characterize severe chronic infections with Epstein Barr Virus and to characterize multiple aspects of the chronic fatigue syndrome. To date this research project has involved nearly 150 patients. Included are 7 patients who were diagnosed with severe chronic EBV infections on the basis of clinical, historical, molecular and serologic features. Detailed immunologic, neurologic, endocrinologic, and psychologic studies are being conducted on selected patients with chronic fatigue. To date we have found no consistent abnormality in the chronic fatigue patients although some can be shown to have immune abnormalities, or depression. We continue open therapeutic trials of tricyclic or MAO inhibitor compounds. During the past year we completed an initial set of studies of the pituitary adrenal responsiveness to corticotropin releasing hormone and to ACTH. We found statistically significant reductions in cortisol levels and ACTH responsiveness to CRH. These led us to propose that there is a novel neuroendocrine effect that may indicate deficient central CRH release. Since CRH induces CNS arousal, these neuroendocrine findings suggest a new mechanism whereby the lethargy of Chronic Fatigue Syndrome patients may be explained. During the past year we explored prolonged intravenous acyclovir and recombinant gamma interferon as treatments for selected patients with life threatening complications of chronic EBV infection. The results are mixed.